OA is clearly associated with cartilage aging, but aging does not inevitably cause OA. Here, we aim to identify eariy aging-related chondrocyte abnormalities that provide a foundation upon which OA is then triggered or accelerated. Fundamental means by which cells normally resolve stress include proteostasis responses such as the unfolded protein response (UPR), which restores equilibrium to the stressed ER via a reprogrammed proteome, rich in chaperones and protein folding catalysts. The UPR also regulates oxidative stress responses, inflammation, and cell fate (normally promoting autophagy, but promofing apoptosis when damaged proteins exceed ER folding capacity). Three UPR signaling/proteolytic cascades are triggered by dissociation of distinct ER membrane proteins from the chaperone GRP78, each culminating in CHOP expression that successfully resolves the UPR, restoring normal protein synthesis and potentially promoting autophagy as opposed to apoptosis. Experimental UPR gain of function and loss of function have triggered cartilage pathology. Furthermore, UPR impairment is linked with aging and degenerative diseases in multiple tissues. We observe impaired CHOP expression in aging and OA cartilages. Moreover, GRP78, which dampens the UPR and inhibits apoptosis, is deficient in early OA, whereas, CHOP and GRP78 are induced by biomechanical stress in normal chondrocytes. Our central hypothesis is that impairment of the UPR due to deficient CHOP and GRP78 in articular chondrocytes are eariy changes of aging cartilage that renders cartilage more susceptible to OA development and progression. We specifically aim to: (1) Test the hypothesis that baseline impairment of the CHOP and GRP78 expression, particularly in the superficial zone, is a fundamental change of aging in articular cartilage and linked with autophagy; (2) Test the hypothesis that impaired CHOP and GRP78 responses to biomechanical and oxidative stress in aging cartilage promotes matrix loss, apoptosis, and decreased autophagy; and (3) Test the hypothesis, in complementary studies of mice, that CHOP deficiency promotes superficial zone chondrocyte dysfunction, matrix loss, and decreased autophagy in vitro, and aging and instability-induced OA in vivo.